The overarching hypothesis of this proposal is that combined type ADHD, as defined by population-based criteria, is a distinct form of ADHD resulting from a combination of genetic and environmental factors creating a distinct developmental profile of neurophysiological functioning, brain structure, motor coordination problems and autistic-like symptomatology. The specific goal of this project is to replicate and expand current studies suggesting important gene-environment interactions in the development of combined type ADHD. Previous investigators have demonstrated that the risk for ADHD is increased in the presence of maternal smoking during pregnancy and certain genotypes of dopamine pathway genes (including the DRD4, dopamine transporter and CHRNA4 genes). Recently, we tested for the interaction of maternal smoking with these candidate genes and have demonstrated marked gene-environment interaction effects which increases the likelihood of developing combined type ADHD from 2.5 to 15-fold. In the current study we will recruit a new sample of 200 epidemiologically ascertained sibling pairs discordant for the presence of combined type ADHD, as defined by population-based criteria. The sibling pairs will be extensively studied for psychopathology, prenatal and early postnatal exposures to maternal, paternal and second hand smoke as well as maternal substance use and abuse. The DRD4, SLC6A3 and CHRNA4 genes will be resequenced in these new sibling pairs and our original sample of 100 dizygotic twin pairs. Using a combination of in silico and in vitro approaches, functional DNA sequence variations in these three genes will be identified. Our primary hypotheses are that maternal smoking during pregnancy and child genotype at the DRD4, DAT and CHRNA4 loci will demonstrate interactive effects on risk of combined type ADHD as well as autistic and motor coordination symptomatology. These effects will be larger for newly defined functional sequence changes. Paternal smoking during pregnancy and second hand smoking exposure during early life will further increase risk. This study takes advantage of an existing epidemiological set of families with four or more full siblings characterized for ADHD and autistic symptoms, allowing the efficient identification of discordant sibling pairs as well as allowing estimates of the impact of any findings in the general population. Subjects of this project could also serve as a longitudinal population-based cohort for extension of our findings of gene-environment interactions to structural and functional imaging as well as neuropsychological studies. PUBLIC HEALTH RELEVANCE: This study takes advantage of an existing epidemiological set of families with four or more full siblings characterized for Attention Deficit/Hyperactivity Disorders (ADHD) and autistic symptoms which allow the efficient identification of discordant sibling pairs and estimates of the impact of prenatal smoking and candidate gene variants in the general population. Functional candidate gene sequence variations will be identified and correlated with clinical features. These research findings could provide important public health information about children, adolescents and adults who have such disorders and the impact these diseases have on the fields of child-development, genetics and environmental toxicology.